WO2024184369A1

WO2024184369A1 - Formulation for the buccal administration of a biocompatible reverse micelle system

Info

Publication number: WO2024184369A1
Application number: PCT/EP2024/055773
Authority: WO
Inventors: Léa BALAN; Jean-Claude Maurel; Abdelkader MOURI
Original assignee: Medesis Pharma SA
Current assignee: Medesis Pharma SA
Priority date: 2023-03-06
Filing date: 2024-03-06
Publication date: 2024-09-12
Anticipated expiration: 2025-09-06

Abstract

The present invention relates to reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55 and a further vegetable oil. The invention also relates to the preparation method of said reverse micelle system, their use and pharmaceutical composition comprising the same.

Description

FORMULATION FOR THE BUCCAL ADMINISTRATION OF A BIOCOMPATIBLE

REVERSE MICELLE SYSTEM

FIELD OF THE INVENTION

The present invention relates to a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, and a further vegetable oil, said system being adapted for a buccal administration in a subject in need thereof. The invention also relates to the medical uses of said reverse micelle system, and pharmaceutical compositions comprising the same.

BACKGROUND OF THE INVENTION

Over the last years, various approaches have been proposed to improve drug delivery to target sites. The main issues are to define the adequate administration of the active ingredient and to guarantee its release in its active form at the targeted site.

For instance, recent discoveries of small RNA such as siRNA, miRNA and RNAa, have opened up wide perspectives in therapeutics. However, these molecules are unstable in biological fluids, in vitro and in vivo, and display poor intracellular penetration and low bioavailability. These critical drawbacks have limited their use in therapeutics. Consequently, clinical applications of these nucleic acids have required chemical modifications with the aim of retaining their capacity to knockdown protein expression while increasing their stability and cellular penetration. Research groups have also applied the nanotechnology approach to improve their delivery, to overcome most barriers that hindered the development of nucleic acids delivery-based therapies. To improve bioavailability, many researchers have also attempted to use alternative routes of administration: ocular, skin, oral, intramuscular. Those attempts have not been entirely satisfactory so far. In the patent EP2549980, the inventors have developed a reverse micelle system capable of crossing mucosa and allowing the vectorization of such nucleic acids to target sites. Similarly, in the patent EP2550020, inventors uncovered a reverse micelle system able to cross mucosa and allow vectorization of metal ions to target sites. The stability of microemulsions containing high quantities of metal is not always satisfactory to allow their development as delivery systems for drugs and/or dietetic compounds for example. Inventors previously uncovered that the incorporation of lipids, in particular in specific amounts, in the formulation of microemulsions comprising higher doses of metal ions surprisingly triggered an important increase in their stability.

The reverse micelle systems mentioned above in the prior art are based on sterols, acylglycerols, phospholipids or sphingolipids, with a specific content of lipids, and comprise at least one active ingredient. However, the inventors found that the administration of these known system was negatively affected by the occurrence of gelling upon contact with an aqueous medium, such as saliva. The gelling is particularly present when administered through the buccal route, yet it is the preferred administration route as it is less invasive than the rectal route.

In addition, it appeared that the higher the ratio phospholipid or sphingolipid/acylglycerol, the more the system will gel in an aqueous medium. Yet, when said reverse micelle systems comprise large/medium- sized active ingredients, it is usually necessary to increase the ratio phospholipid or sphingolipid/acylglycerol to provide a better solubilisation of the active ingredients.

The gelling of the reverse micelle system leads to a loss of efficiency of said system. In particular, the gelling negatively impacts the absorption through the mucosa and the bioavailability of the active ingredient. Furthermore, the gelling decreases patients compliance because the gelled product has an unpleasant texture and a bad taste.

There is thus a real need of formulations which would allow the buccal administration of reverse micelle system based on sterols, acylglycerols, phospholipids or sphingolipids, and improve the compliance and the bioavailability of the active ingredient. Such formulations would thus avoid the occurrence of gelling while retaining the stability and efficacy of the system.

SUMMARY OF THE INVENTION

The present invention relates to an improvement of the bioavailability of water-soluble active ingredients using reverse micelle system based on sterols, acylglycerols, phospholipids or sphingolipids when administered through the mucosa, in particular the buccal mucosa. The reverse micelle system according to the invention is able to cross mucosa and cellular membranes, even in high humidity environments such as the buccal mucosa. It allows vectorization of both small and large-molecules to target sites. The invention also relates to the improvement of organoleptic properties of said reverse micelle system, allowing a better acceptance of the system when used buccally in humans. It is advantageously useful in the pharmaceutical fields.

Surprisingly, the inventors found that increasing the contents of unsaturated fatty acids, in particular long-chain unsaturated fatty acids, in the reverse micelle system delays or prevents the phase transition to a gel, while maintaining the stability and efficiency of the system for the delivery of the active ingredient. The unsaturated fatty-acids are preferably unsaturated long-chain fatty acids such as oleic acid and linoleic acid. The inventors also found that vegetable oils are an appropriate source of unsaturated fatty acids in the context of the invention. The addition of a vegetable oil in the reverse micelle system does not interfere with the stability and the efficacy of said system and delays or avoids the gelling in an aqueous medium.

The invention also relates to an aromatization of the reverse micro-emulsion. The inventors have selected aromas that do not interfere with the stability of the system and succeed in improving the compliance. In particular, the inventors found that hydrophobic (non-polar) aromas and/or aromas have shown to be more effective than hydrophilic aromas.

The first object of the invention is thus a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, and a further vegetable oil.

The invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.

The invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating pathologies of the CNS such as bipolar disorders and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.

The invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating Alzheimer disease, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.

The invention further relates to a reverse micelle system as defined above, for use for treating a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.

The invention further relates to a reverse micelle system as defined above, for use for treating inflammatory cytokine storms triggered by aggressive viruses, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.

The invention further relates to a reverse micelle system as defined above, for use for treating a subject exposed to radiation therapy of cancers and/or preventing radiation damage in a subject exposed to radiation therapy of cancers, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.

The invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic disease infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation, wherein the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid" (siNA), "short interfering RNA" (siRNA), "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA).

The invention further relates to a reverse micelle system as defined above, for use in inhibiting the expression of pathological or overexpressed genes, wherein the water-soluble active ingredient is siRNA’s. In particular, the invention further relates to a reverse micelle system as defined above, for use for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases, neuromuscular genetic diseases, metabolic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation, wherein the water-soluble active ingredient is siRNA’s.

The invention further relates to a reverse micelle system as defined above, for use in the treatment of Huntington’s disease, wherein the water-soluble active ingredient is P42 TAT.

The invention further relates to a reverse micelle system as defined above, for use in decorporating at least one radionuclide and/or treating at least one metal intoxication, wherein the water-soluble active ingredient is CaNa3DTPA.

The invention also relates to a pharmaceutical composition comprising a reverse micelle system that comprises sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, and a further vegetable oil; and at least a pharmaceutically acceptable vehicle. In a preferred embodiment, said pharmaceutical composition is for buccal administration.

The invention also relates to a buccal delivery system comprising a reverse micelle system that comprises sterol, acylglycerol, alcohol, water, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, a further vegetable oil, and a water- soluble active ingredient intended to be administered within the buccal mucosa. The invention also relates to the use of a vegetable oil, preferably a vegetable oil comprising unsaturated long-chain fatty acids, in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water- soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.

According to a further aspect, the present invention relates to a method for the preparation of a reverse micelle system according to the invention, wherein the method comprises the following steps:

(a) Contacting (i) sterol, (ii) acylglycerol, (iii) phospholipid or sphingolipid, (iv) alcohol, (v) vegetable oil, (vi) water, and (vii) at least one water-soluble active ingredient, and;

(b) Stirring mixture obtained in step (a), at 40 °C or less, and for a time sufficient to obtain formation of reverse micelles, said stirring being preferably carried out mechanically.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Partial pseudotemary phase diagram of the Peceol/Olive oil/B- sitosterol/Lecithin/Ethanol/Water system at Peceol/olive oil ratio of 85/15. The colored area represents the monophasic region (W/O microemulsion). The temperature was 25 °C.

Figure 2: Dynamic viscosity of the system Peceol/Olive oil/B-sitosterol/Lecithin/Ethanol as a function of water content along the dilution L27 in the phase diagram, at different Olive oil/(Olive oil + Peceol) ratios : x= 0 (oil free microemulsion), x=0,l and x=0,15. The temperature was 25°C.

Figure 3: Lithium blood concentration in rats after a single dose administration of 0,6 mg of Li/kg by buccal deposit of Nanolithium formulation at two different x ratios : x = 0 and x = 0, 1 (x = Olive oil/(Olive oil + Peceol)).

Figure 4: Lithium brain concentration in rats after a single dose administration of 0,6 mg of Li/kg by buccal deposit of Nanolithium formulation at two different x ratios : x = 0 and x = 0, 1 (x = Olive oil/(Olive oil + Peceol)).

Figure 5: Dynamic viscosity of the system Peceol/Vegetable oil/B-sitosetrol/Lecithin/Ethanol as a function of water content along the dilution L27 in the phase diagram, for olive oil, soya oil and sesame oil at x=0,15 (x represents the ratio oil/(oil + Peceol)). The temperature was 25°C.

DETAILED DESCRIPTION OF THE INVENTION

Definition As used herein, the terms "mucosa" and "mucosal" refer to a mucous tissue such as of the respiratory, digestive, or genital tissue.

As used herein, “mucosal delivery”, “mucosal administration” and analogous terms refer to the administration of a composition through a mucosal tissue.

As used herein, “buccal administration” is intended for delivering drugs/active ingredients within/through the buccal mucosa in order to achieve a local or systemic effect.

As used herein, the terms “treatment”, “treat” or “treating” refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease. In certain aspects, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other aspects, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease.

As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to an animal, preferably to a mammal, even more preferably to a human, including adult and child. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others.

The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule or a product.

As used herein, the terms "active principle", "active ingredient" and "active pharmaceutical ingredient" are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect.

As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a disease or disorder, or to cure or to attenuate the effects of a disease or disorder.

As used herein, the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of the disease. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the disease, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the disease to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.

Unless otherwise specified, the percentage values used in the present invention are weight percentages with respect to the total weight of the named compounds or reverse micelle system.

The reverse micelle system A first object of the invention is a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, and a further vegetable oil.

The reverse micelle system according to the invention is characterized as a microemulsion comprising a dispersion of water-nanodroplets in oil. The dispersion is stabilised by two surfactants (acylglycerol, more preferably a diacylglycerol and a phospholipid, more preferably phosphatidylcholine, or a sphingolipid) and a co-surfactant (alcohol) that are most likely at the water/oil interface. The reverse micelle phase can be defined as a system wherein water forms the internal phase and the hydrophobic tails of the lipids form the continuous phase. Reverse micelles containing oil(s), surfactant(s), co-surfactant(s), and an aqueous phase are also characterized as water-in-oil microemulsions. These microemulsions are visually limpid.

Generally, the size of micelles according to the invention is very small, more particularly, it is less than 10 nm; more specifically it is less than 8 nm and more preferably less than 6 nm. The size may vary with the quantity of added water and phospholipid or sphingolipid. The present invention relates more particularly to reverse micelles presenting a correlation distance from 3 nm to 10 nm, more preferably from 3.5 nm to 6.5 nm, in particular from 3,7 nm to 5,7 nm, including around 4,7 nm.

The reverse micelles size can be characterized by various methods known by the one skilled in the art, including Small Angle X-Ray Scattering (SAXS), Neutrons Scattering, Transmission Electron Microscopy (TEM), or Dynamic Light Scattering (DLS)

The ratios of the lipidic constituents (including sterol, acylglycerol and phospholipid or sphingolipid) in this reverse micelle system according to the invention can vary. For instance, the weight ratio sterol/acylglycerol can range from 0,01 to 0,1 more particularly from 0,025 to 0,05. The weight ratio phospholipid or sphingolipid/acylglycerol can range from 0,05 to 0,55, in particular from 0,06 to 0,30.

The weight of phospholipid or sphingolipids respectively corresponds to the total weight of the mixture of phospholipids or sphingolipids, for instance the weight of lecithin, used in the formulation. Similarly, the weight of acylglycerol corresponds to the total weight of the mixture usually containing an acylglycerol, or a mixture of acylglycerols, with glycerol and fatty acids derived from said acylglycerol(s).

The compounds of the reverse micelle system can be analysed by appropriate means. More specifically, sterols can be identified by gas chromatographic analysis and acylglycerol by high- performance liquid chromatography (HPLC), in particular with a light scattering detector, on a silica column, in the presence of an eluent, e.g. isocratic acetonitrile. Gas chromatography can also be used to analyse diacylglycerols. Phospholipids and sphingolipids can be analysed by high-performance liquid chromatography (HPLC), with a diol column with a light scattering detector.

Reverse micelles are dynamic systems. Brownian motion causes perpetual collisions of micelles, which lead to coalescence of micelles and exchange of the aqueous phases. Separation and regeneration of micelles occur and allow chemical reactions between different solutions. The exchange rate between micelles increases in particular with temperature, the length of hydrocarbon chains of the surfactant, and the ratio water/surfactant.

Reverse micelles may exist in the system of the invention as different structural organizations, such as spheres, cylinders, branched cylinders or locally lamellar structure, for instance.

The reverse micelles of the invention allow active ingredients included therein to be administered and transported to target sites, in particular cells. In particular, the reverse micelle system of the invention ensures absorption of the ingredients to be delivered across mucosa, in particular across buccal mucosa. Also, reverse micelles of the present invention provide an important bioavailability with low variability of absorption.

The compounds included in the reverse micelle system, as well as their contents, are described in more details below.

Examples of amounts for different components of the reverse micelle system according to the invention are the following: (percentages by weight according to the total weight of the reverse micelle system)

The reverse micelle system may comprise from 1% to 30%, preferably from 1% to 20%, in particular from 5% to 15% phospholipids or sphingolipids, preferably lecithin.

The reverse micelle system may comprise from 0. 1% to 20%, preferably from 1% to 15%, in particular from 5% to 15% water.

The reverse micelle system may comprise from 5%to 20%, preferably from 5%to 15%, more preferably 5% to 12% alcohols, preferably ethanol.

The reverse micelle system may comprise from 0.82% to 4.5% sterol.

The reverse micelle system may comprise from 30% to 90%, preferably from 50% to 90% acylglycerol.

Components of the reverse micelle system

Vegetable oils

The reverse micelle system according to the invention comprises a vegetable oil. The terms vegetable oil, also called plant oil, are used to refer to a non-animal oil of plant origin, in particular from all or part of a plant. The vegetable oil is preferably a pharmaceutically acceptable vegetable oil.

As explained above, the use of a vegetable oil in the reverse micelle system delays or prevents the phase transition to a gel in an aqueous medium, while maintaining the stability and efficiency of the system for the delivery of the active ingredient.

In the context of the invention, the vegetable oil preferably comprises unsaturated mediumchain fatty acids and/or unsaturated long-chain fatty acids.

As used herein, the terms “long -chain fatty acids” refer to fatty acids containing from 13 to 21 carbon atoms.

As used herein, the terms “medium-chain fatty acids” refer to fatty acids containing from 6 to 12 carbon atoms such as caproic acid, caprylic acid, capric acid or lauric acid.

In a preferred embodiment, the vegetable oil comprises unsaturated long-chain fatty acids. In particular, the vegetable oil is rich in unsaturated long-chain fatty acids. Namely, the vegetable oil comprises at least 50%, preferably at least 70%, unsaturated long -chain fatty acids, by weight of the total weight of the vegetable oil.

In the context of the invention, the terms “unsaturated long -chain fatty acids” refer to fatty acids containing 13-21 carbon atoms and comprising at least one C=C double bond. The C=C double bonds can give either cis or trans isomers. In particular, the unsaturated long-chain fatty acids can be for example Myristoleic acid (C14), Palmitoleic acid (C16), Sapienic acid (C16), Oleic acid (C18), Elaidic acid (Cl 8), Vaccenic acid (Cl 8), Linoleic acid (Cl 8), Linoelaidic acid (Cl 8), a-Linolenic acid (Cl 8), Arachidonic acid (C20), and Eicosapentaenoic acid (C20). Preferably, the unsaturated long-chain fatty acids comprises 18 to 21 carbon atoms, more preferably 18 carbon atoms. In a particular embodiment, the unsaturated fatty acid is oleic acid and/or linoleic acid

In a preferred embodiment, the vegetable oil comprises at least 50 %, preferably at least 70%, of oleic acid and/or linoleic acid, by weight of the total weight of the vegetable oil.

In a preferred embodiment, the vegetable oil is selected from the group consisting of olive oil, sunflower oil, safflower oil, soya oil, sesame oil, and mixtures thereof. Preferably the vegetable oil is olive oil. In an advantageous manner, the olive oil used is refined olive oil. The inventor uncovered that refined olive oil contributes to improving the organoleptic properties of the reverse micelle system.

In a preferred embodiment of the invention, the content of the vegetable oil in the reverse micelle system is higher than 3 %, preferably at least 4%, by weight of the total weight of the reverse micelle system. For example, the content of the vegetable oil in the reverse micelle system is between 4% and 20 %, between 5% and 20%, between 6% and 20%, between 7% and 20%, between 8% and 20%, between 9% and 20%, or between 10% and 20%, by weight of the total weight of the reverse micelle system. The content of the vegetable oil in the reverse micelle system can also be for example between 4% and 19 %, between 4% and 18%, between 4% and 17%, between 4% and 16%, between 4% and 17%, between 4% and 16%, between 4% and 15%, between 4% and 14%, between 4% and 13%, between 4% and 12%, between 4% and 11%, or between 4% and 10%, by weight of the total weight of the reverse micelle system. Preferably, the reverse micelle system according to the invention comprises a vegetable oil content of between 4% and 20%, preferably between 6% and 10%, by weight of the total weight of the reverse micelle system.

In a preferred embodiment of the invention, the content of the olive oil in the reverse micelle system is higher than 3 %, preferably at least 4%, by weight of the total weight of the reverse micelle system. For example, the content of the olive oil in the reverse micelle system is between 4% and 20 %, between 5% and 20%, between 6% and 20%, between 7% and 20%, between 8% and 20%, between 9% and 20%, or between 10% and 20%, by weight of the total weight of the reverse micelle system. The content of the olive oil in the reverse micelle system can also be for example between 4% and 19 %, between 4% and 18%, between 4% and 17%, between 4% and 16%, between 4% and 17%, between 4% and 16%, between 4% and 15%, between 4% and 14%, between 4% and 13%, between 4% and 12%, between 4% and 11%, or between 4% and 10%, by weight of the total weight of the reverse micelle system. Preferably, the reverse micelle system according to the invention comprises an olive oil content of between 4% and 20%, preferably between 6% and 10%, by weight of the total weight of the reverse micelle system

It can be noted that below or at a content of 3%, the vegetable oil (in particular the olive oil) cannot avoid the gelling of the reverse micelle system in an aqueous medium, and above a content of 20%, the vegetable oil (in particular the olive oil) leads to a loss of the micelle structure.

Acylglycerols

Acylglycerols used in the reverse micelle system according to the invention can be isolated from the majority of animals, and more preferably plants.

Acylglycerols used according to the invention include mono-, di- and tri -acylglycerols. Preferably, acylglycerols used according to the invention are of the following formula (I):

wherein:

- Ri is an acyl residue of a linear or branched unsaturated fatty acid having between 14 and 24 carbon atoms; - R2 is an acyl residue of a linear or branched unsaturated fatty acid having between 2 and 18 carbon atoms, or a hydrogen atom;

- R3 is an acyl residue of a linear or branched unsaturated fatty acid having between 14 and 24 carbon atoms, or a hydrogen atom.

According to a particular embodiment, Ri or R3, preferably only one of Ri and R3, in particular only Ri, represents an acyl residue of oleic acid (C18: l[cis]-9).

According to a particular aspect, R2 has one unsaturated bond (e.g., ethylenic bond) and has advantageously 18 carbon atoms, preferably R2 is an oleic acid residue (oleoyl group), one of its positional isomers with respect to the double bond (cis-6,7,9,11 and 13) or one of its iso-branched isomers.

According to another particular aspect, Ri represents an oleoyl group.

According to another particular aspect, R2 represents an acetyl group.

According to another particular aspect, R3 is a hydrogen atom.

According to another particular aspect, R2 and R3 are hydrogen atoms.

As a general rule, oil containing a high concentration of oleic acid will be chosen as a useful source of acylglycerols according to the invention. Such oil usually contains a high proportion of acylglycerols useful according to the invention.

According to a particular aspect of the invention, the preferred diglycerols of fatty acids are selected in the group consisting of 1 -monooleate, 1,2-diolein glycerol (also called glycerol 1,2 -dioleate) and 1 -oleoyl -2 -acetyl glycerol.

A certain number of them, and more particularly those which are found to be the most active in the applications sought after, are also available commercially. For instance, glycerol monooleate 40 contains about 32 to 52% of monoacylglycerol, 30 to 50% of diacylglycerol, 5 to 20% of triacylglycerol and is pharmaceutically accepted (European Pharmacopeia (8^th Edition), USP 25/NF20, and Japanese Standard of food Additives). Such product is for instance commercially available by Gattefosse Company under the name Peceol®. In particular, Peceol® may comprise around 45.3 wt% of monoacyl glycerol, around 44.5 wt% of diacylglycerol and around 8.6 wt% of triacyl glycerol (the acyl fraction of Peceol® is mainly made of oleoyl - usually around 80% of the acyl residue is oleoyl fraction).

According to the present description, the weight of acylglycerol corresponds to the total weight of the mixture usually containing an acylglycerol, or a mixture of acylglycerols, with glycerol and fatty acids derived from said acylglycerol(s), such as Peceol® described above.

The acylglycerols are preferably incorporated or comprised in the composition or reversemicelle system in an amount by weight ranging from 50 g to 90 g with respect to 100 g of the total weight of the composition or reverse-micelle system according to the invention. The amounts specified herein will be adapted with respect to the other compounds as to correspond more specifically to the weight ratios identified below.

Acylglycerols are natural compounds, and may be extracted and/or derived from renewable vegetable sources. Their use is thus favoured in terms of biocompatibility and environmental concerns when compared to synthetic compounds.

Sterol

The reverse micelle system according to the invention comprises at least one sterol, preferably natural sterol, such as cholesterol or phytosterol (vegetable sterols). Sitosterol and cholesterol are the preferred sterols that can be present in a reverse micelle system according to the invention. Preferably, the reverse micelle system comprises sitosterol, such beta-sitosterol.

Sitosterol and cholesterol are commercially available. More particularly, commercial sitosterol, which is extracted from soya, can be used. In such a product, the sitosterol generally represents from 50 to 80% by weight of the product and is generally found in a mixture with campesterol and sitostanol in respective proportions in the order of 15% each. Commercial sitosterol, which is extracted from a variety of pine called tall oil, can also be used. In general, it will be possible to use sitosterol in mixture with sitostanol. Preferably, said mixture comprises at least 50% sitosterol by weight of the mixture.

The sterols are preferably incorporated or comprised in the composition or reverse micelle system in an amount by weight ranging from 0.825 g to 4.5 g with respect to 100 g of the total weight of the composition or reverse micelle system according to the invention. The amounts specified herein will be adapted with respect to the other compounds as to correspond more specifically to the weight ratios identified above and/or below.

Alcohol

The alcohols useful for the preparation of the reverse-micelle system according to the invention are preferably linear or branched mono-alcohols from C2 to C6. Examples of alcohols are ethanol, 1- butanol, 2-butanol, 3 -methyl- 1 -butanol, 2 -methyl- 1 -propanol, 1 -pentanol, 1 -propanol, 2-propanol and any mixtures thereof.

In a particular embodiment of the invention, alcohol is ethanol. Ethanol is generally an ethanol- water solution, wherein the ethanol amount is from about 90% to 99% by volume. In a more particular embodiment, ethanol is absolute or anhydrous alcohol (that refers to ethanol with low water content). There are various grades with maximum water contents ranging from 1% to a few parts per million (ppm) levels. Absolute ethanol is preferred. The alcohol is preferably incorporated or comprised in the composition or reverse micelle systems in an amount by weight ranging from 5 g to 12 g with respect to 100 g of the total weight of the composition or reverse micelle system according to the invention.

Phospholipids are formed of a glycerol linked to 2 fatty acids and to a phosphate group. The variability of phospholipids relies on the fatty acids that are attached to the glycerol and on the chemical groups that are susceptible to link to the phosphate group. Phospholipids are, with sphingolipids, the major lipidic constituents of biological membranes.

Among phospholipids useful in the present invention may be cited phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylinositol, and phosphatidylcholine .

In a particular embodiment, the phospholipid is phosphatidylcholine. Phosphatidylcholine is also known as l,2-diacyl-glycero-3 -phosphocholine or PtdCho.

Phosphatidylcholine is formed from a choline, a phosphate group, a glycerol and two fatty acids. It is actually a group of molecules, wherein the fatty acid compositions varies from one molecule to another. Phosphatidylcholine may be obtained from commercial lecithin that contains phosphatidylcholine in weight concentrations of 20 to 98%. The lecithin preferably used for the preparation of the reverse micelles according to the invention is preferably Lipoid SI 00® and contains phosphatidylcholine at a concentration of more than 90%, in particular more than 94%.

Sphingolipids are a class of lipids derived from the aliphatic amino alcohol sphingosine. Among sphingolipids that may be used in the present invention may be cited acylsphingosin, sphingomyelins, glycosphingolipids, and gangliosides.

The reverse micelles system of the invention may comprise phospholipids, sphingolipids, or a mixture of both types of compounds.

According to a specific embodiment, the reverse micelles system of the invention comprises phospholipids.

According to a specific embodiment, the reverse micelles system of the invention comprises lecithin.

The weight ratio phospholipid and/or sphingolipid/acylglycerol in compositions or reverse micelle systems according to the invention is from 0,05 to 0,55 in particular from 0,06 to 0,30. The phospholipids or sphingolipids are preferably incorporated or comprised in the composition or reverse micelle system in an amount by weight ranging from 1 g to 30 g, preferably from 5 to 20 g with respect to 100 g of the total weight of the composition or reverse micelle system according to the invention. The amounts specified herein will be adapted with respect to the other compounds as to correspond more specifically to the weight ratios identified above.

Water

The water useful for the preparation of the reverse micelle system according to the invention is preferably purified water; more particularly distilled or deionized water.

Water is preferably incorporated or comprised in the composition in an amount by weight ranging from 1 g to 15 g, preferably from 5 g to 15 g, with respect to 100 ml of the total volume of the composition or reverse micelle system according to the invention.

One of ordinary skill in the art will adapt the amount of phospholipid or sphingolipid in the systems to the desired amount of water. For instance, increasing amount of water should imply increasing amount of phospholipid or sphingolipid in the systems.

Water-soluble active ingredient

The reverse micelle system of the invention comprises at least one water-soluble active ingredient.

In a particular aspect of the invention, the water-soluble active ingredient is selected from the group consisting of metal ions, chelating and/or sequestering agents, nucleic acids, oligonucleotides, small molecules, biomolecules, and peptides. More particularly, the water-soluble active ingredient is selected from the group consisting of metal ions (such as lithium, manganese), chelating and/or sequestering agents (such as DTP A), nucleic acids/antisense oligonucleotides, nucleotides, peptides (such as P42 TAT), small molecules or biomolecules.

In a particular aspect of the invention, the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic, manganese, and mixtures thereof. Metal ions may be metal salts. By way of examples, particularly useful metal salts according to the invention are selected from sulfates, hydrates, halides, in particular chlorides, citrates, carbonates and any other water-soluble salt. Preferably the metal ion is lithium or manganese, in particular lithium citrate or manganese sulfate. In a particular aspect of the invention, the water-soluble active ingredient is lithium, preferably lithium citrate. In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.

In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating pathologies of the CN S such as bipolar disorder, and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.

In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating Alzheimer disease, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.

In a particular aspect, the invention further relates to a method for preventing and/or treating a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, in a subject in need thereof, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of the reverse micelle system as defined above, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.

In a particular aspect, the invention further relates to a method for preventing and/or treating pathologies of the CNS such as bipolar disorder, and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, or disease due to a prion infection, in a subject in need thereof, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of the reverse micelle system as defined above, wherein the water-soluble active ingredient is lithium, preferably lithium citrate. In a particular aspect, the invention further relates to a method for preventing and/or treating Alzheimer disease in a subject in need thereof, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of the reverse micelle system as defined above wherein the water-soluble active ingredient is lithium, preferably lithium citrate.

In a particular aspect, the invention further relates to the use of the reverse micelle system as defined above, in the manufacture of a medicament for the prevention and/or the treatment of a disease or disorder selected from the group consisting of pathologies of the central nervous system, neurodegenerative diseases, autoimmune diseases, type 2 diabetes, insulin resistance, metabolic syndrome, cancers such as respiratory tumors or acute promyelocytic leukemia, acquired immunodeficiency syndromes, cancerology, osteoporosis, diseases linked to oxidative stress, bipolar disorders, depression, and inflammatory disorders, wherein the water-soluble active ingredient is a metal ion, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese.

In a particular aspect, the invention further relates to the use of the reverse micelle system as defined above, in the manufacture of a medicament for the prevention and/or the treatment of pathologies of the CNS such as bipolar disorder, and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, ,or disease due to a prion infection, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.

In a particular aspect, the invention further relates to the use of the reverse micelle system as defined above, in the manufacture of a medicament for the prevention and/or the treatment of Alzheimer disease, wherein the water-soluble active ingredient is lithium, preferably lithium citrate.

Examples of metals adapted to other types of activity are indicated below: antimony or tin, if the treatment of autoimmune diseases concerning, in particular, the nervous system, for example multiple sclerosis and cancerology, is desired, gold, in autoimmune diseases affecting the locomotor system, for example in rhumatoid arthritis, vanadium in diabetes type 2, insulin resistance and metabolic syndrome, ruthenium or palladium in respiratory tumors or neoplasias, tin, in acquired immunodeficiency syndroms, selenium in cancerology, strontium in osteoporosis, arsenic in cancers, in particular acute promyelocytic leukemia, manganese in disease linked to oxidative stress. In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use for treating a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.

In a particular aspect, the invention further relates to a method for treating a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.

The invention further relates to a method for treating inflammatory cytokine storms triggered by aggressive viruses, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.

The invention further relates to a method for treating a subject exposed to radiation therapy of cancers and/or preventing radiation damage in a subject exposed to radiation therapy of cancers, said method comprising the administration, preferably buccal administration, to a subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate.

In a particular aspect, the invention further relates to the use of a reverse micelle system as defined above, wherein the water-soluble active ingredient is manganese, preferably manganese sulfate, for the manufacture of a medicament for the treatment of a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation.

The invention further relates to the use of a reverse micelle system as defined above, wherein the water- soluble active ingredient is manganese, preferably manganese sulfate, for the manufacture of a medicament for the treatment of inflammatory cytokine storms triggered by aggressive viruses.

The invention further relates to the use of a reverse micelle system as defined above, wherein the water- soluble active ingredient is manganese, preferably manganese sulfate, for the manufacture of a medicament for the treatment of a subject exposed to radiation therapy of cancers and/or the prevention of radiation damage in a subject exposed to radiation therapy of cancers.

The metal ions and the associated medical uses are preferably as disclosed in the international application WO2011/117333.

In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use for treating and/or preventing paludism, wherein the water-soluble active ingredient is methylene blue.

The invention further relates to a method for treating and/or preventing paludism in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water- soluble active ingredient is methylene blue.

The invention further relates to the use of a reverse micelle system as defined above, wherein the water- soluble active ingredient is methylene blue, for the manufacture of a medicament for the treatment and/or the prevention of paludism.

In a particular aspect of the invention, the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid" (siNA), "short interfering RNA" (siRNA), "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA). In a particular aspect of the invention, the water-soluble active ingredient is siRNA’s.

In the context of the invention, “Nucleic acid” includes any DNA (deoxyribonucleic acid) and RNA (ribonucleic acid). The terms include single-stranded RNA, single -stranded DNA, double-stranded RNA, double -stranded DNA, plasmid DNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, aptamers, as well as nucleic acids comprising non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. One can cite for instance gapmers.

By “oligonucleotide” is meant a nucleic acid comprising from 5 to 100 nucleotides, preferably from 10 to 90 nucleotides, more preferably from 13 to 80 nucleotides, more particularly from 13 to 25 nucleotides.

The terms “antisense oligonucleotides”, "short interfering nucleic acid" (siNA), "short interfering RNA" (siRNA), "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", “miRNA”, “micro RNA”, “RNA activation” (RNAa), “short hairpin RNA” (shRNA), and “aptamers”, as used herein, refer to any nucleic acid molecule capable of modulating gene expression by up or down regulating (for instance gene silencing) target protein expression in a sequence-specific manner. In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use for preventing and/or treating genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation, wherein the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid" (siNA), "short interfering RNA" (siRNA), "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA).

In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use in inhibiting the expression of pathological or overexpressed genes, wherein the water-soluble active ingredient is siRNA’s. In particular, the invention further relates to a reverse micelle system as defined above, for use for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic disease, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation.

In a particular aspect, the invention further relates to a method for preventing and/or treating genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water- soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid" (siNA), "short interfering RNA" (siRNA), "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA).

In a particular aspect, the invention further relates to a method for inhibiting the expression of pathological or overexpressed genes in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above wherein the water-soluble active ingredient is siRNA’s. In particular, the invention further relates to a method for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic disease, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above. In a particular aspect, the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid" (siNA), "short interfering RNA" (siRNA), "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA), for the manufacture of a medicament for the prevention and/or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic diseases, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation.

In a particular aspect, the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is siRNA’s, for the manufacture of a medicament for the inhibition of the expression of pathological or overexpressed genes. In particular, the invention further relates to the use of a reverse micelle system as defined above, for the manufacture of a medicament for use for the prevention and /or treatment of genetic diseases, cancers, neurodegenerative diseases in particular neurodegenerative genetic disease, neuromuscular genetic diseases, metabolic diseases in particular metabolic genetic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation.

The nucleic acid and the associated medical uses are preferably as disclosed in the international application WO2011/117334.

In a particular aspect of the invention, the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal, preferably selected from the group consisting of DTPA, bisphosphonates, Prussian blue, EDTA, Trientine, D-penicillamine, Deferoxamine, BAL, DMSA, DMPS, Phytic acid, Hydroxypyridonates (HOPO), mercaptoacetyltriglycine (MAG3), chelating peptides, derivatives thereof and combinations thereof. Preferably the appropriate compound for chelating and/or sequestering at least one radionuclide and/or metal is CaNa3DTPA.

In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use as an imaging agent and/or as a diagnosis agent, wherein the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal.

In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use in the treatment of at least one disease linked to the accumulation and/or overload of at least one radionuclide or metal in a patient in need thereof, wherein the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal.

In a particular aspect, the invention further relates to a method for the treatment of at least one disease linked to the accumulation and/or overload of at least one radionuclide or metal in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above wherein the water- soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal.

In a particular aspect, the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is a compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal, for the manufacture of a medicament for the treatment of at least one disease linked to the accumulation and/or overload of at least one radionuclide or metal in a subject in need thereof.

The diseases (or pathologies) linked to the accumulation and/or overload of at least one metal may vary depending on the metal and radiation exposure (duration and/or amount), it can include Wilson’s disease; haemochromatosis; or a pathology or symptom due to a metal accumulation from an external origin such as anxiety, memory loss, depression, suicidal tendencies, loss of strength and coordination, bleeding gums and tooth loss, abdominal cramps, diarrhea or chronic constipation, abnormal heart rate or blood pressure, repeated infections or cancer, chronic migraines, allergies, dermatitis, heart palpitations, sinus congestion, loss of appetite, chronic obesity and Alzheimer's disease. The diseases (or pathologies) linked to the accumulation and/or overload of at least one radionuclide may vary depending on the radiation exposure (duration and/or amount), it can include gastrointestinal disorders, such as nausea or vomiting, symptoms related to falling blood counts, such as predisposition to infection or bleeding, neurological disorders, or different types of cancers (such as blood cancers or thyroid cancer).

In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use for use in decorporating at least one radionuclide and/or treating at least one metal intoxication, wherein the water-soluble active ingredient CaNa3DTPA.

In a particular aspect, the invention further relates to a method for decorporating at least one radionuclide and/or treating at least one metal intoxication in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above, wherein the water-soluble active ingredient CaNa3DTPA. In a particular aspect, the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient CaNa3DTPA, for the manufacture of a medicament for use for decorporating at least one radionuclide and/or treating at least one metal intoxication.

The compound appropriate for chelating and/or sequestering at least one radionuclide and/or metal, and the associated medical uses are preferably as disclosed in the international application WO2015/124581.

In a particular aspect of the invention, the water-soluble active ingredient is a peptide, preferably P42 TAT. In a particular aspect, the invention further relates to a reverse micelle system as defined above, for use in the treatment of Huntington’disease, wherein the water-soluble active ingredient is P42 TAT. The invention further relates to a method for the treatment of Huntington’disease in a subject in need thereof, said method comprising the administration, preferably buccal administration, to the subject in need thereof of an effective amount of a reverse micelle system as defined above wherein the water- soluble active ingredient is P42 TAT.

In a particular aspect, the invention further relates to the use of a reverse micelle system as defined above wherein the water-soluble active ingredient is P42 TAT, for the manufacture of a medicament for the treatment of Huntington’disease.

In a particular aspect of the invention, the reverse micelle system comprises cyano-bridged metal nanoparticles. In a particular aspect, the invention further relates to the reverse micelle system according to the invention, for use for being substituted by and/or sequestering radionuclide and/or metal cations, wherein said reverse micelle system comprises cyano-bridged metal nanoparticles.

The cyano-bridged metal nanoparticles and the associated uses are preferably as disclosed in the international application W02017/005899.

In a particular aspect of the invention, the water-soluble active ingredient is preferably a small molecule. In the context of the invention a small molecule refer preferentially to molecules smaller than 1 KDalton.

Hydrophobic aroma

In a particular embodiment of the invention, the reverse micelle system further comprises a hydrophobic aroma compound.

The reverse micelle system have a pronounced taste of rancid oil. This unpleasant taste can be responsible for patient non-compliance, particularly in young subjects or in the case of long-term treatment. Aromas can thus be used to mask this taste but must not interfere with the stability and effectiveness of the reverse micelle system.

Aromas used for the present invention are hydrophobic aromas, preferably lipophilic aromas.

In the context of the invention, a molecule, namely an aroma, is said to be hydrophobic or lipophilic when it is soluble in fats, but insoluble in water. A hydrophobic molecule does not have the capacity to create hydrogen bonds with water molecules. It is also often said to be apolar, or of low polarity, which means that it cannot create electrostatic interactions with water. Indeed, the solubility of a molecule in a solvent depends generally on the interactions it can have with the solvent. A hydrophobic molecule is therefore a molecule that cannot physically interact with water.

In an advantageous manner, the hydrophobic aromas used according to the invention are selected in the group consisting of menthol, peppermint essential oil, eucalyptol, and mixtures thereof. Aromas are preferably incorporated in the composition in an amount by weight ranging from 0, 1 g ,to 4,0 g preferably from 0,5 g to 2,0 g, with respect to 100 g of the total weight of the composition or reverse micelle system according to the invention.

Other components

The reverse micelle system according to the invention may comprise any type of additional components. The amounts of the components of the reverse micelle system can be adapted by anyone of ordinary skill in the art depending on the desired properties for the phase or system, such as visual appearance, viscosity, and/or concentration of active agent for instance.

In a preferred embodiment, the reverse micelle system does not comprise liposomes.

In an embodiment of the invention, the amounts of the components of the reverse micelle system are adjusted so that the reverse micelle system is in the form of a liquid. One of ordinary skill in the art can adapt the relative amounts of acylglycerol, sterol, lecithin, ethanol and water in the reverse micelle systems for obtaining a liquid with the desired properties, such as the visual appearance, the viscosity, and/or the concentration of the active agent for instance.

Preparation of the reverse micelle systems of the invention

In a particular embodiment, the invention relates to a method for preparing reverse micelles as defined above wherein said method comprises the following steps:

(b) Stirring mixture obtained in step (a), at 40 °C or less, and for a time sufficient to obtain formation of reverse micelles.

The obtained and recovered reverse micelles are then particularly useful as a delivery system for a water-soluble active ingredient. Step (b) of the process is of particular importance since it allows reverse micelles to be obtained, said reverse micelles being then useful as a transport system for delivering active ingredients into the target sites. Target sites may for instance be cells of a specific tissue.

In a particular embodiment, the water-soluble active ingredient is first solubilised in water, preferably purified water, to form an aqueous mixture. Said aqueous mixture is then introduced into the oily mixture (according to step (a)). The oily mixture preferably comprises at least a sterol, an acylglycerol, a phospholipid or sphingolipid, an alcohol and the further vegetable oil. All these compounds are as defined above.

Stirring of the mixture obtained by step (a) is carried out at a temperature less than or equal to 40°C, preferably ranging from 15 °C to 40°C, more preferably from 25 °C to 40 °C, or more specifically from 30 °C to 37 °C, for a time sufficient to form of reverse micelles. The time sufficient can vary in particular upon the used stirring techniques, i.e., mechanical stirring. The time of mechanical stirring is more specifically the time needed to convert the initial mixture into a visually transparent reverse micelle solution.

One skilled in the art knows how to select excipients or components that may be used along with the composition according to the present invention in order to keep their beneficial properties. In particular, the presence of glycerol can, when introduced in large amount, prevent the formation of reverse micelles or break the reverse micelle system. More specifically, no more than 2.5%, and preferably no glycerol (percent expressed by weight of glycerol / weight of acylglycerol) is used for the preparation of the reverse micelles of the present invention.

In a particular embodiment, when the reverse micelle system further comprises a hydrophobic aroma, the aroma can also be introduced in step (a).

Other compounds can be introduced in step (a). One can cite for instance colouring agents.

In an advantageous manner, the compounds cited above or the commercially available mixtures containing them are the only ingredients introduced to prepare the micelle system and consequently the only ones present in the micelle system of the invention.

Stirring of step (b) may for instance be performed by mechanical stirring. The common materials may be propellers whose fast movements generate turbulences and swirls allowing interpenetration of particles and formation of reverse micelles within the mixture. Mechanical stirring speed is preferably ranging from 100 to 2 000 r/minute, more preferably from 300 to 700 r/minute. The implemented volumes, device, and stirring speed depend on and should be adapted with the reactants and amounts thereof. Temperature is more specifically ranging from 15°C to 40°C, or from 25 °C to 40 °C, or even more specifically from 30 °C to 37 °C.

Pharmaceutical composition comprising the reverse micelle system

The invention also relates to a pharmaceutical composition comprising the reverse micelle system according to the invention, and at least a pharmaceutically acceptable vehicle.

In particular, the pharmaceutical composition of the invention comprises a therapeutically effective amount of the reverse micelle system.

The pharmaceutical composition of the invention is preferably for mucosal administration, more preferably for buccal administration. According to a specific embodiment, the pharmaceutical composition according to the invention comprises from 5 to 20 g of phospholipid or sphingolipid with respect to 100 g of composition, and from 5 to 15 g of water with respect to 100 ml of composition.

The term “pharmaceutically acceptable vehicle” is intended to include any and all carriers, solvents, diluents, excipients, adjuvants, dispersion media, coatings, antibacterial and antifungal agents, absorption agents and the like, well-known by the person skilled in the art, and compatible with administration in mammals and in particular human subjects. Other additives well-known to the person skilled in the art such as stabilisers, drying agents, binders or pH buffers may also be used. Preferred excipients in accordance with the invention promote adherence of the finished product to the mucosa.

According to a particular embodiment, the pharmaceutical composition is in the form of vial, airless bottle, non-airless bottle, unidose syringe, stick liquid, a capsule, a caplet, an aerosol, a spray, a solution or a soft elastic gelatin capsule.

The invention also relates to a buccal delivery system comprising a reverse micelle system according to the invention or a composition according to the invention, wherein the water-soluble active ingredient is intended to be administered within the buccal mucosa.

Administration of the reverse micelle systems

The reverse micelle system or pharmaceutical composition of the invention can be administered in different ways, in particular via the oral, nasal, vaginal or rectal route, preferably with a buccal, nasal, vaginal or digestive absorption, or more generally via mucosal tissue absorption. In a preferred embodiment, the reverse micelle system or pharmaceutical composition of the invention is administered by buccal route. In a specific embodiment, the reverse micelle system or pharmaceutical composition of the invention is administered via mucosa.

As used herein, “Mucosal delivery", "mucosal administration" and analogous terms include, but are not limited to, the delivery of a composition through preferably buccal administration, bronchi, gingival, lingual, nasal, oral, vaginal, rectal, and gastro-intestinal mucosal tissue. Administration according to the invention is more preferably carried out via buccal mucosa.

Uses

A further aspect of the invention is the use of a vegetable oil, preferably a vegetable oil comprising long-chain fatty acids, in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium. In particular, the invention relates to the use of more than 3 %, preferably at least 4%, of a vegetable oil in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.

In particular, the invention relates to the use of more than 3 %, preferably at least 4%, of an olive oil in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.

The vegetable oil and its content are preferably as defined above, in particular in the section “vegetable oil”.

EXAMPLES

The following examples are intended to exemplify the operation of the present invention but not to limit its scope.

Example 1: Preparation of reverse micelle formulated with peptide P42TAT

0,3384 g of lecithin were dissolved in 0,2030 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,0564 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,1354 g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 1,2588 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture.

0,264 g of a P42TAT solution containing 3,00 mg of P42TAT were added to 1,992 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form reverse micelles containing 1200 pg of P42TAT/ml.

Example 2: Preparation of reverse micelle formulated with lithium citrate used as treatment for Alzheimer disease.

3,52 g of lecithin were dissolved in 2,11 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,59 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 1,88 g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 12,39 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture. 1

3,0 g of a lithium citrate solution containing 15,0 mg of lithium were added to 20,5 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form reverse micelles containing 600 pg of Li/ml.

Example 3: Preparation of reverse micelle formulated with Calcium Diethylenetriaminepentaacetic Acid trisodium (CaNa3DTPA).

0,2850 g of lecithin were dissolved in 0,1710 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,0475 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,1140 g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 1,0625 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture.

0,220 g of a CA-DTPA solution containing 20 mg of CaNa3DTPA were added to 1,680 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form reverse micelles containing 10 mg of CaNa3DTPA/ml.

Example 4: Study of the reverse micelle system of the invention

Methods:

1) Vegetable oil selection:

Three pharmaceutical vegetable oils have been selected to be incorporated into the reverse micelle system: i) refined sesame oil (39% of oleic acid and 41% of linoleic acid), ii) refined soybean oil (21% of oleic acid and 55% of linoleic acid) and iii) refined olive oil (78% of oleic acid and 5,5% of linoleic acid). In a vial, 6 gr of reverse micelle system has been titrated by oil until apparition of turbidity.

2) Phase diagram:

The Peceol®/olive oil/B-sitosterol/lecithin/ethanol/water system was explored by the construction of pseudo-ternary phase diagram at constant weight ratio of Peceol® to olive oil (85/15). In this study, the ethanol (cosurfactant) / lecithin (surfactant) weight ratio was kept constant (40/60). To prepare samples, Peceol® was stirred gently at 37°C in a mixture of lecithin, B-sitosterol and ethanol (prepared separately by weighing the surfactant, sterol and alcohol into a glass vial containing a magnetic stirrer until a transparent and homogenous yellow solution was obtained. To avoid evaporation of ethanol during stirring, all glass vials used were tightly stopped with a screw-cap. After cooling down to about 25 °C, the required amounts of olive oil were added to the mixture. Depending on (Peceol® + olive oil) concentrations, different stock solutions were obtained, these lipid mixtures were diluted with the aqueous phase (purified water). The 1 -phase microemulsion boundary was predetermined by visual observation with the appearance of turbidity and phase separation. All experiments were carried out at 25 °C. 3) Rheology:

Rheology measurements were performed using an Anton Paar Rheometer MCR92, Cone plates with 6 cm in diameter and an angle of 0,5° was used. Temperature was maintained at 25°C± 0. 1°C. Shear rate measurements were performed between 0.01 and 1000s ¹. A sample volume of 1 ml was used.

4) Pharmacokinetic study:

Sprague Dawley rats, 3 rats per group, were administered with 600pg metal lithium/kg by muco-buccal route with 2 formulations of lithium in reverse micelles. These products were administered slowly with a micropipette and adapted conical tips into the mouth to cover the maximal mucosa surface.

Blood samples (400 pL per time-point) were collected at 2h, 3h, 4h and 24h after the treatment in the sinus retro-orbital using a capillary tube and stored in test tubes with anticoagulant. Animal were sacrificed 24 hours after the treatment and the brain will be collected, weighed, divided in two hemispheres and each half of brain will be stored frozen at target temperature of -20°C until shipment. Lithium concentration in blood and brain were determined by Inductively Coupled Plasma Mass Spectrometry (I CP -MS).

Results and discussion:

1 ) Vegetable oil selection:

The aim of this study is to evaluate the impact of oil incorporation on the stability of microemulsion after dilution. Three pharmaceutical oils: sesame, soybean and olive oils have been tested by the titration method. Oil has been added gradually to the microemulsion until apparition of turbidity. The results shown that 26,3 wt% of sesame oil, 26,6 wt% of soybean and 29,2 wt% of olive oil can be incorporated into the microemulsion.

2) Phase diagram:

The solubilization efficiency of the five -component system Peceol/olive oil/B-sitosterol/lecithin/ethanol was evaluated by the preparation of partial pseudo-ternary phase diagram at constant Peceol/olive oil ratio of 85/15 (Fig 1). The colored area in the explored zone of the phase diagram represents the monophasic reverse microemulsion region. As can be observed in the phase diagram, the extension of the microemulsion zone toward the water rich comer increases slightly in the Peceol rich region up to 10wt% of lecithin/ethanol and then increases gradually with the amount of lecithin/ethanol to reach a maximum at 24 wt% of water. It could be noted, that the area of the olive oil based microemulsion and the olive oil free microemulsion represents respectively 23% and 23,3% of the total explored zone in the phase diagram. The impact of olive oil incorporation on the extent of the monophasic domain studied in comparison with the olive oil free system doesn’t seem to be significant. However, the phase behavior and the in-situ gelling properties of the system were significantly affected by addition olive oil in the water rich region of the phase diagram. Upon water dilution, the olive oil free microemulsions demixed first into a clear liquid (fully hydrated microemulsion) with excess water and then forms a turbid gel with high capacity of drug retention, formulations with higher values of consistency and viscosity impose resistance to the movement of internal phase of the system and which can impact strongly their drug release properties. Our finding show that adding olive oil to the system disturbed the formation of this gel liquid crystal in the water rich region of the phase diagram, increased the dilution rate of the microemulsion and consequently its ability to sustain drug release upon contact with saliva in the oral cavity.

3) Rheology:

In order to obtain a more detailed insight about the effect of olive oil adding on the stability and rheological properties of microemulsions upon dilution with aqueous solution, visual control and dynamic viscosity of the olive oil based microemulsions were carried out along the dilution line L27 (Fig 1) as a function of olive oil/(olive oil + Peceol) ratio and compared to the olive oil free system.

As can be observed in the Fig 2, the viscosity of microemulsions in the single-phase region increased slowly with increasing water content. This increase in viscosity is mainly attributed to the hydration and swelling mechanism of reverse micelles. No significant effect of olive oil adding on the viscosity of microemulsion is observed in this domain, the viscosity values of microemulsions at 10% of water for X=0, X=0,l and X=0,15 are respectively 137 mPas, 134 mPas and 132 mPas. However, in the biphasic region, results of viscosity measurement of the olive oil free system achieved in the upper microemulsion phase (water saturated microemulsion) showed a strong increment in viscosity to reach a value of 1065 mPas. The shift in the viscosity beyond the water saturation point cannot be interpreted in terms of water content (dispersed phase volume) and may be related to a structural transition mechanism from microemulsion to liquid crystalline phases (gels). Microemulsions exhibit lower viscosities whereas liquid crystalline phases exhibit higher viscosities and complex rheology. However, no shift in viscosity has been observed with the olive oil based microemulsions in the biphasic region, viscosity value doesn’t exceed 690 mPas (for x=0,l) and 604 mPas (for x=0,15). All microemulsion samples exhibited a Newtonian flow behavior with a linear dependence of the shear stress as a function of shear rate. These results suggest that the addition of olive oil could prevent the in-situ gelling of formulation related to the phase transition to the liquid crystalline phases, and may increase the stability of the microemulsion upon contact with water in the oral cavity.

4) Pharmacokinetic study:

Preparation of reverse micelle formulated (with olive oil) with lithium citrate used as treatment for Alzheimer disease

1,4250 g of lecithin was dissolved in 0,8550 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,2375 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,610 g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 5,1725 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture. 1,2 g of a lithium citrate solution containing 8,12 mg of lithium were added to 8,3 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form reverse micelles containing 600 pg of Li/ml.

Preparation of reverse micelle formulated (without olive oil) with lithium citrate used as treatment for Alzheimer disease

1,4250 g of lecithin was dissolved in 0,8550 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,2375 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. 5,7825 g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture. 1,2 g of a lithium citrate solution containing 8,12 mg of lithium were added to 8,3000 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form reverse Results

The aim of this study was to evaluate the pharmacokinetic of metal lithium in the blood and the delivery of lithium in the brain as a function of reverse microemulsion formulated with and without olive oil, composition of formulation and procedure of preparation are detailed above. The formulations were administrated via muco-buccal route.

As can be observed in figure 3 and 4, results shown that incorporation of olive oil in the system has increased the blood concentration of lithium at timepoint 2 hours (Cmax) from 134 ng/g (olive oil free microemulsion) to 207ng/g (olive oil based microemulsion), that represents an increase of 54% of blood lithium concentration in rat. Additionally, results allow delivery of greater amount of lithium in brain by using olive oil, lithium brain concentration has increased of around 38,5 %, from 70,5 ng/g to 97,7 ng/g (in presence of olive oil).

Example 5: Texture assessment of olive oil based reverse micelle system (microemulsion) in contact with buccal mucosa

For the sensory and acceptance formulation evaluation, 10 microemulsions (reverse micelle system according to the invention) containing increasing quantity of olive oil (up to 10 wt%) were tested. The formulations were applied by each participant on the buccal mucosa (in contact with cheek) using plastic pipette of approximately 1,5 mb of microemulsion so that each participant could evaluate the same amount of product.

The formulation composition and preparation are detailed hereafter (Table 1), the results are presented in Table 2: 1,4250 g of lecithin was dissolved in 0,8550 g absolute ethanol by magnetic stirring at 300 r/min for 15 minutes at room temperature. 0,2375 g B-sitosterol were added thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. (Y) g of olive oil were thereto and magnetic stirring at 300 r/min for 15 minutes at room temperature. (X) g of glycerol monooleate were then added and magnetic stirring was carried out at 500 r/min for 45 minutes at 37°C to form oil mixture. 1,2 g of purified water were added to 8,3 g of the oil mixture and stirred at room temperature by magnetic stirring at 700 r/min for 15 minutes to form empty reverse micelles.

Table 1

Olive oil free microemulsion has been used as control is this study.

Table 2: results of texture assessment of olive oil based microemulsions in contact with buccal mucosa

The formulation including 3% oil prevents partially the gelling but leads to the formation of a persistent film on the palate and inside the cheeks. Above this percentage the formulations do not form a gel in contact with saliva into the oral cavity.

Example 6: Use of vegetable oil selected from soya oil, sesame oil and olive oil The effect of three different vegetable oils (olive oil, soya oil and sesame oil) adding on the stability and rheological properties of microemulsions upon dilution with aqueous solution has been studied along the dilution line L27 (similarly to Example 4). Visual control and dynamic viscosity of the vegetable oil based microemulsions were carried out at fixed ratio x = 0,15 (x=(oil/(oil + Peceol)) and compared to the vegetable oil free system (x=0). As can be observed in the Fig 5, the viscosity of microemulsions in the single-phase region increased slowly with increasing water content. This increase in viscosity could be attributed mainly to the hydration and swelling mechanism of reverse micelles. No significant effect of type of vegetable oil added on the viscosity of microemulsion is observed in this domain, the viscosity values of microemulsions at 10% of water for olive oil, soya oil, sesame oil are respectively 132 mPas, 136 mPas and 137 mPas (compared to free oil microemulsion viscosity corresponding to 137 mPas). However, in the biphasic region, results of viscosity measurement of vegetable oil based microemulsions achieved in the upper microemulsion phase (water saturated microemulsion) showed a slight increase of viscosity of oil based microemulsion compared to the free oil system where strong increment in viscosity and gel formation were observed. At water fraction of 40%, viscosity value of olive oil, soya oil and sesame oil based microemulsions does not exceed respectively 488 mPas, 347 mPas and 329 mPas where free vegetable oil microemulsion viscosity has reached 1158 mPas.

These results suggest that the addition of vegetable oil such as olive oil, soya oil or sesame oil, could prevent the in-situ gelling of formulation related to the phase transition to the liquid crystalline phases, and may increase the stability of the microemulsion upon contact with water in the oral cavity.

Claims

1. Reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55 and a further vegetable oil.

2. The reverse micelle system according to claim 1, wherein the content of the further vegetable oil is higher than 3 %, preferably at least 4%, more preferably between 4% and 20%, by weight of the total weight of the reverse micelle system.

3. The reverse micelle system according to claim 1 or 2, wherein the further vegetable oil comprises unsaturated long-chain fatty acids, preferably oleic acid and/or linoleic acid, more preferably at least 50 % of oleic acid and/or linoleic acid.

4. The reverse micelle system according to any one of claims 1 to 3, wherein the further vegetable oil is selected from the group consisting of olive oil, sunflower oil, safflower oil, soya oil, sesame oil, and mixtures thereof, preferably olive oil.

5. The reverse micelle system according to any one of claims 1 to 4, comprising phospholipid, preferably lecithin.

6. The reverse micelle system according to any one of claims 1 to 5, further comprising a hydrophobic aroma compound, preferably selected in the group consisting of menthol, peppermint essential oil, eucalyptol, and mixtures thereof.

7. The reverse micelle system according to any one of claims 1 to 6, being adapted for buccal administration.

8. The reverse micelle system according to any one of claims 1 to 7, wherein the water-soluble active ingredient is selected from the group consisting of metal ions, chelating and/or sequestering agents, nucleic acids, oligonucleotides, small molecules, cyano-bridged metal nanoparticles, biomolecules, and peptides.

9. The reverse micelle system according to any one of claims 1 to 8, wherein the water-soluble active ingredient is selected from the group consisting of -metal ions, preferably selected in the group consisting of lithium, zinc, niobium, vanadium, selenium, molybdenum, chromium, antimony, tin, gold, ruthenium, palladium, platinum, strontium, arsenic and manganese, preferably lithium or manganese, more preferably lithium citrate or manganese sulfate;

- P42 TAT;

- CaNa3DTPA; and

- a nucleic acid, preferably an oligonucleotide, more preferably selected from the group consisting of "short interfering nucleic acid" (siNA), "short interfering RNA" (siRNA), "short interfering nucleic acid molecule", "short interfering oligonucleotide molecule", “miRNA”, “micro RNA”, and “short hairpin RNA” (shRNA), preferably wherein the water-soluble active ingredient is siRNA.

10. The reverse micelle system as defined in claim 9, wherein the water-soluble active ingredient is a metal ion, for use in preventing and/or treating a disease or disorder selected from the group consisting of pathologies of the central nervous system (CNS) such as bipolar disorder and/or neurodegenerative diseases such as Huntington’s disease, Parkinson disease, Alzheimer disease, amyotrophic lateral sclerosis, multiple sclerosis, prevention of dementia, or disease due to a prion infection; or wherein the water-soluble active ingredient is a metal ion, for use for preventing and/or treating inflammatory cytokine storms triggered by aggressive viruses, or for treating a subject exposed to radiation and/or preventing radiation damage in a subject at risk for exposure to radiation or radiation therapy of cancers; or wherein the water-soluble active ingredient is a nucleic acid, for use for preventing and/or treating genetic diseases, cancers, neurodegenerative diseases, neuromuscular genetic diseases, metabolic diseases, infectious and/or inflammatory diseases, or diseases or disorders due to cell proliferation; or wherein the water-soluble active ingredient is CaNa3DTPA, for use in decorporating at least one radionuclide and/or treating at least one metal intoxication.

11. The reverse micelle system as defined in claim 9, for use in preventing and/or treating Alzheimer disease wherein the water-soluble active ingredient is a lithium salt, preferably lithium citrate.

12. The reverse micelle system as defined in claim 9, for use in the treatment of Huntington disease, wherein the water-soluble active ingredient is P42 TAT.

13. A pharmaceutical composition comprising a reverse micelle system as defined in any one of claims 1 to 12 and at least a pharmaceutically acceptable vehicle.

14. A buccal delivery system comprising a reverse micelle system as defined in any one of claims 1 to 12 or a pharmaceutical composition as defined in claim 13, wherein the water-soluble active ingredient is intended to be administered within the buccal mucosa.

15. Use of a vegetable oil, preferably a vegetable oil comprising unsaturated long-chain fatty acids, in a reverse micelle system comprising sterol, acylglycerol, alcohol, water, water-soluble active ingredient, and phospholipid or sphingolipid, wherein the weight ratio phospholipid or sphingolipid/acylglycerol range from 0.05 to 0.55, for avoiding the occurrence of gelling of said reverse micelle system in an aqueous medium.